Abstract Limiting immune-mediated damage following transplantation while maintaining protective immunity requires precise regulation of the immune system. A major challenge is the activation of alloreactive T lymphocytes, which is carefully controlled by the balance of costimulatory and coinhibitory signals T cells receive. The CD28/CTLA-4 pathway is the prototypic co-signaling pathway in T cells, with CTLA-4 co-inhibition acting as the counter-signal to CD28 costimulation as they bind the same receptors, CD80 and CD86. Immunomodulation via blockade of this pathway is a promising approach to prevent inappropriate T cell activation in the setting of transplantation. Belatacept, which binds to CD80/86, is the first costimulation blocker to be FDA approved for use in clinical transplantation and offers significantly improved long-term graft function and fewer toxicities compared to calcineurin inhibitors (CNIs). Use of Belatacept was associated with increased rates of EBV-associated post-transplant lymphoproliferative disorder (PTLD), which is normally kept under strict control by the immune surveillance activities of virus-specific CD8+ T cells. The idea that CD28-mediated signals are required for sufficient EBV-specific CD8+ T cell responses and control of viral recrudescence has recently come into question. Two recent studies have suggested that blocking CD28 is fundamentally different than blocking CD80/CD86 with regard to EBV-specific adaptive immune responses and viral control. Recently, a reagent that selectively targets CD28, while leaving CTLA-4-mediated inhibition intact, has been developed. These anti-CD28 domain antibodies have been shown to be roughly five times more potent than Belatacept against CD86- driven T cell proliferation and to be a more potent inhibitor of graft rejection when compared to CTLA-4 Ig treatment. Given the potent immunosuppressive effects of the anti-CD28 dAb, understanding the impact of selective CD28 blockade on protective immunity is an important clinical question. Additionally, this comparison has never been made in the setting of pre-transplant chronic kidney disease (CKD) in which patients have a well-documented immune dysregulation leading to increased susceptibility to infections, immune-activation-associated inflammation, and poor responses to vaccines. To this end, we plan to directly compare the effects of selective CD28 blockade vs. CTLA-4 Ig on protective immune responses to both murine cytomegalovirus (CMV) as well as MHV-68, a murine homolog of EBV, in both healthy WT mice and mice affected by CKD. Determining the precise effects of CD28 vs. CD80/86 blockade on the generation, maintenance, and functionality of CMV- and MHV-specific CD8+ T cell responses in these settings will provide mechanistic insight and inform the development of novel selective CD28 blockers for use in clinical transplantation.